The effects of high density lipoprotein (HDL) and low density lipoprotein (LDL) on the formation of 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE), thromboxane (TX) B2 and 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT) in washed rabbit platelets were examined. HDL had a powerful inhibitory effect on 12-HETE formation, while it produced only a small increase in TXB2 and HHT formation. LDL did not affect the formation of 12-HETE, TXB2 and HHT. These results suggest that HDL is a selective inhibitor of platelet 12-lipoxygenase and may play a protective role in atherogenesis by preventing the generation of 12-HETE.